ABSTRACT The annual incidence of sudden cardiac death (SCD) in the US ranges between 200,000 - 300,000 and the vast majority occur due to fatal arrhythmia. A consensus has emerged in the field for delineation of multiple predictors that could be combined as a risk score to enhance SCD risk stratification. In a population of 562 patients implanted with ICDs, we have previously reported that prolonged ventricular repolarization measured as increased duration of the QRS interval on the 12-lead ECG (?QRSd) was a predictor of recurrent ventricular arrhythmias, consistent with findings reported by others. Now our preliminary findings from a separate study in the general population indicate that ?QRSd can be observed in the absence of severe LVSD and is a potential predictor of SCD in the broader community. The goal of this application is to evaluate the potential of QRSd as a predictor of SCD risk in the general population. The Oregon Sudden Unexpected Death Study is an ongoing population-based case-control study in the Portland, Oregon metro area (pop. approx. 1,000,000). Using clinical information and DNA samples from 1100 SCD cases and 1100 matched controls, we propose to test the hypothesis that prolonged ventricular depolarization independently contributes to the ventricular arrhythmia substrate in CAD and that this substrate is modulated by intermediate risk phenotypic traits such as type 2 diabetes as well as the individual's genomic profile. Candidate gene variants identified will be validated in a separate population of 1200 SCD cases. Our specific aims are: 1. To determine the independent contribution of QRSd toward risk of SCD. 2. To identify phenotypic determinants of ?QRSd and their contribution to SCD risk. 3. To evaluate the role of ventricular depolarization-affecting gene variants in susceptibility to SCD among patients with CAD. An established and ongoing population-based case-control study and the ready availability of expertise in clinical electrophysiology, epidemiology and genomics will facilitate this detailed evaluation of how QRSd may enhance SCD risk prediction. Given the wide applicability and relatively low cost of the 12-lead ECG, any enhancement of risk stratification of SCD by this proposal is likely to have significant clinical relevance. PUBLIC HEALTH RELEVANCE: Project Narrative Sudden cardiac death (SCD) is a public health problem of significant magnitude, with an annual incidence estimated between 200,000 - 400,000 in the US. Prolongation of cardiac depolarization as measured on the electrocardiogram (QRS interval duration) appears to confer an increased risk of SCD, but this clinical finding is currently not used for risk stratification. Clarifying the determinants of SCD risk associated with prolonged QRS duration has the potential for rapid clinical and scientific application, leading to enhanced risk stratification for SCD in the general population, as well as focused therapy for patient subgroups with prolonged ECG intervals, and could potentially reduce the population burden of SCD.